Evaluierung des natürlich vorkommenden Autoantikörpers gegen α-Synuclein als potentieller Biomarker für das idiopathische Parkinsonsyndrom

Das idiopathische Parkinsonsyndrom (IPS) gehört mit einer Prävalenz von 100-200/100.000 zu den häufigsten neurodegenerativen Erkrankungen. Das klinische Erscheinungsbild setzt sich aus Tremor, Rigor, Bradykinese und einer posturalen Haltungsinstabilität zusammen. Das histopathologische Korrelat der...

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Main Author: Wolf, Elias
Contributors: Dodel, Richard (Prof. Dr. med.) (Thesis advisor)
Format: Dissertation
Published: Philipps-Universität Marburg 2012
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138. Tokuda T, Salem SA, Allsop D, Mizuno T, Nakagawa M, Qureshi MM, Locascio JJ, Schlossmacher MG, El-Agnaf OM. 2006. Decreased alpha-synuclein in cerebrospinal fluid of aged individuals and subjects with Parkinson's disease. Biochem Biophys Res Commun 349(1):162-166.

139. Brettschneider S, Morgenthaler NG, Teipel SJ, Fischer-Schulz C, Burger K, Dodel R, Du Y, Moller HJ, Bergmann A, Hampel H. 2005. Decreased serum amyloid beta(1-42) autoantibody levels in Alzheimer's disease, determined by a newly developed immuno-precipitation assay with radiolabeled amyloid beta(1-42) peptide. Biol Psychiatry 57(7):813-816.

140. Fahn S. 2003. Description of Parkinson's disease as a clinical syndrome. Ann N Y Acad Sci 991:1-14.

141. Tokuda T, Qureshi MM, Ardah MT, Varghese S, Shehab SA, Kasai T, Ishigami N, Tamaoka A, Nakagawa M, El-Agnaf OM. 2010. Detection of elevated levels of alpha-synuclein oligomers in CSF from patients with Parkinson disease. Neurology 75(20):1766-1772.

142. El-Agnaf OM, Salem SA, Paleologou KE, Curran MD, Gibson MJ, Court JA, Schlossmacher MG, Allsop D. 2006. Detection of oligomeric forms of alpha- synuclein protein in human plasma as a potential biomarker for Parkinson's disease. FASEB J 20(3):419-425.

143. Mollenhauer B, Cullen V, Kahn I, Krastins B, Outeiro TF, Pepivani I, Ng J, Schulz- Schaeffer W, Kretzschmar HA, McLean PJ, Trenkwalder C, Sarracino DA, Vonsattel JP, Locascio JJ, El-Agnaf OM, Schlossmacher MG. 2008. Direct quantification of CSF alpha-synuclein by ELISA and first cross-sectional study in patients with neurodegeneration. Exp Neurol 213(2):315-325.

144. Rascol O, Ferreira JJ, Thalamas C, Galitsky M, Montastruc JL. 2001. Dopamine agonists. Their role in the management of Parkinson's disease. Adv Neurol 86:301-309.

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146. Masliah E, Rockenstein E, Adame A, Alford M, Crews L, Hashimoto M, Seubert P, Lee M, Goldstein J, Chilcote T, Games D, Schenk D. 2005. Effects of alpha- synuclein immunization in a mouse model of Parkinson's disease. Neuron 46(6):857-868.

147. Shults CW, Oakes D, Kieburtz K, Beal MF, Haas R, Plumb S, Juncos JL, Nutt J, Shoulson I, Carter J, Kompoliti K, Perlmutter JS, Reich S, Stern M, Watts RL, Kurlan R, Molho E, Harrison M, Lew M, Parkinson Study G. 2002. Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline. Arch Neurol 59(10):1541-1550.

148. Flower L, Ahuja RH, Humphries SE, Mohamed-Ali V. 2000. Effects of sample handling on the stability of interleukin 6, tumour necrosis factor-alpha and leptin. Cytokine 12(11):1712-1716.

149. Mäßig eingeschränkt. Eindeutige und frühzeitige Ermüdung. Bewegung kann gelegentlich unterbrochen werden.

150. Crowther JR. 1995. ELISA: theory and practice. Totowa, New Jersey: Humana Press Inc.

151. Engvall E, Perlmann P. 1971. Enzyme-linked immunosorbent assay (ELISA).

152. Tanner CM, Aston DA. 2000. Epidemiology of Parkinson's disease and akinetic syndromes. Curr Opin Neurol 13(4):427-430.

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157. Fehlen einer Haltungsreaktion; würde fallen, wenn er nicht vom Untersucher aufgefangen würde.

158. Gehen schwierig, benötigt aber wenig oder keine Hilfe; eventuell leichtes Trippeln, kurze Schritte oder Propulsion.

159. Geht langsam, kann einige kurze Schritte schlurfen, jedoch keine Festination oder Propulsion.

160. Satake W, Nakabayashi Y, Mizuta I, Hirota Y, Ito C, Kubo M, Kawaguchi T, Tsunoda T, Watanabe M, Takeda A, Tomiyama H, Nakashima K, Hasegawa K, Obata F, Yoshikawa T, Kawakami H, Sakoda S, Yamamoto M, Hattori N, Murata M, Nakamura Y, Toda T. 2009. Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson's disease. Nat Genet 41(12):1303-1307.

161. Rigidität (Geprüft bei passiver Bewegung der großen Gelenke am sitzenden Patienten. Zahnradphänomen kann ignoriert werden) – Nacken und je rechte und linke obere Extremität, je rechte und linke untere Extremität. 0. Fehlt.

162. Geringe Amplitude persistierend; oder mäßige Amplitude, aber nur intermittierend auftretend.

163. Gosavi N, Lee HJ, Lee JS, Patel S, Lee SJ. 2002. Golgi fragmentation occurs in the cells with prefibrillar alpha-synuclein aggregates and precedes the formation of fibrillar inclusion. J Biol Chem 277(50):48984-48992.

164. Große Amplitude; beim Essen störend.

165. Große Amplitude, die meiste Zeit vorhanden.

166. Hardy J. 2006. Has the amyloid cascade hypothesis for Alzheimer's disease been proved? Curr Alzheimer Res 3(1):71-73.

167. Manoussakis MN, Tzioufas AG, Silis MP, Pange PJ, Goudevenos J, Moutsopoulos HM. 1987. High prevalence of anti-cardiolipin and other autoantibodies in a healthy elderly population. Clin Exp Immunol 69(3):557-565.

168. Du Y, Wei X, Dodel R, Sommer N, Hampel H, Gao F, Ma Z, Zhao L, Oertel WH, Farlow M. 2003. Human anti-beta-amyloid antibodies block beta-amyloid fibril formation and prevent beta-amyloid-induced neurotoxicity. Brain 126(Pt 9):1935-1939.

169. Dodel R, Hampel H, Depboylu C, Lin S, Gao F, Schock S, Jackel S, Wei X, Buerger K, Hoft C, Hemmer B, Moller HJ, Farlow M, Oertel WH, Sommer N, Du Y. 2002. Human antibodies against amyloid beta peptide: a potential treatment for Alzheimer's disease. Ann Neurol 52(2):253-256.

170. Zecca L, Wilms H, Geick S, Claasen JH, Brandenburg LO, Holzknecht C, Panizza ML, Zucca FA, Deuschl G, Sievers J, Lucius R. 2008. Human neuromelanin induces neuroinflammation and neurodegeneration in the rat substantia nigra: implications for Parkinson's disease. Acta Neuropathol 116(1):47-55.

171. Underwood JR, Pedersen JS, Chalmers PJ, Toh BH. 1985. Hybrids from normal, germ free, nude and neonatal mice produce monoclonal autoantibodies to eight different intracellular structures. Clin Exp Immunol 60(2):417-426.

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175. ANHANG Literaturverzeichnis XVIII Monsonego A, Maron R, Zota V, Selkoe DJ, Weiner HL. 2001. Immune hyporesponsiveness to amyloid beta-peptide in amyloid precursor protein transgenic mice: implications for the pathogenesis and treatment of Alzheimer's disease. Proc Natl Acad Sci U S A 98(18):10273-10278.

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177. Neff F, Wei X, Nolker C, Bacher M, Du Y, Dodel R. 2008. Immunotherapy and naturally occurring autoantibodies in neurodegenerative disorders. Autoimmun Rev 7(6):501-507.

178. Li Q, Gordon M, Cao C, Ugen KE, Morgan D. 2007a. Improvement of a low pH antigen- antibody dissociation procedure for ELISA measurement of circulating anti- Abeta antibodies. BMC Neurosci 8:22.

179. Desplats P, Lee HJ, Bae EJ, Patrick C, Rockenstein E, Crews L, Spencer B, Masliah E, Lee SJ. 2009. Inclusion formation and neuronal cell death through neuron-to- neuron transmission of alpha-synuclein. Proc Natl Acad Sci USA 106(31):13010- 13015.

180. Youden WJ. 1950. Index for rating diagnostic tests. Cancer 3(1):32-35.

181. Baumgarth N, Tung JW, Herzenberg LA. 2005. Inherent specificities in natural antibodies: a key to immune defense against pathogen invasion. Springer Semin Immunopathol 26(4):347-362.

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183. Sommer N, Oertel WH. 2004. Intravenous immunoglobulins containing antibodies against beta-amyloid for the treatment of Alzheimer's disease. J Neurol Neurosurg Psychiatry 75(10):1472-1474.

184. Olanow CW, Prusiner SB. 2009. Is Parkinson's disease a prion disorder? Proc Natl Acad Sci U S A 106(31):12571-12572.

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186. Langsam; kann mehr als einen Versuch benötigen.

187. Leichte Verlangsamung und/oder Verringerung der Amplitude.

188. Leicht oder nur erkennbar bei Aktivierung durch spiegelbildliche oder andere Bewegungen.

189. Eggert KM, Oertel WH. 2008. Leitlinie Parkinson-Syndrome Diagnostik und Therapie / hrsg. von der Expertengruppe des Kompetenznetz Parkinson. Teilausg. von: Diener, H. C.: Leitlinien für Diagnostik und Therapie in der Neurologie. Stuttgart: Georg Thieme Verlag.

190. Olanow CW, Perl DP, DeMartino GN, McNaught KS. 2004. Lewy-body formation is an aggresome-related process: a hypothesis. Lancet Neurol 3(8):496-503.

191. Mäßig verminderte Mimik; Lippen zeitweise geöffnet. 4. Maskenhaftes oder erstarrtes Gesicht mit stark oder völlig fehlendem Ausdruck; der Mund steht mindestens 0,5cm offen.

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197. Mäßige Amplitude, bei Beibehalten der Haltung und bei Bewegung vorhanden.

198. Mäßige Amplitude, die meiste Zeit vorhanden.

199. Mäßig vorgebeugte Haltung; eindeutig abnorm, kann leicht zu einer Seite geneigt sein.

200. Minimal veränderte Mimik, könnte ein normales "Pokergesicht" sein.

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206. Waxman EA, Giasson BI. 2009. Molecular mechanisms of alpha-synuclein neurodegeneration. Biochim Biophys Acta 1792(7):616-624.

207. Goetz CG, Poewe W, Rascol O, Sampaio C, Stebbins GT, Counsell C, Giladi N, Holloway RG, Moore CG, Wenning GK, Yahr MD, Seidl L, Movement Disorder Society Task Force on Rating Scales for Parkinson's D. 2004. Movement Disorder Society Task Force report on the Hoehn and Yahr staging scale: status and recommendations. Mov Disord 19(9):1020-1028.

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210. Chen C, Stenzel-Poore MP, Rittenberg MB. 1991. Natural auto-and polyreactive antibodies differing from antigen-induced antibodies in the H chain CDR3. J Immunol 147(7):2359-2367.

211. Marchalonis JJ, Kaveri S, Lacroix-Desmazes S, Kazatchkine MD. 2002. Natural recognition repertoire and the evolutionary emergence of the combinatorial immune system. FASEB J 16(8):842-848.

212. Elkon K, Casali P. 2008. Nature and functions of autoantibodies. Nat Clin Pract Rheumatol 4(9):491-498.

213. Brundin P, Barker RA, Parmar M. 2010. Neural grafting in Parkinson's disease Problems and possibilities. Prog Brain Res 184:265-294.

214. Lashuel HA, Hartley D, Petre BM, Walz T, Lansbury PT, Jr. 2002. Neurodegenerative disease: amyloid pores from pathogenic mutations. Nature 418(6895):291.

215. Uversky VN. 2007. Neuropathology, biochemistry, and biophysics of alpha-synuclein aggregation. J Neurochem 103(1):17-37.

216. Merbl Y, Zucker-Toledano M, Quintana FJ, Cohen IR. 2007. Newborn humans manifest autoantibodies to defined self molecules detected by antigen microarray informatics. J Clin Invest 117(3):712-718.

217. Nicht ganz aufrecht, leicht vorgebeugte Haltung; könnte bei einem älteren Menschen normal sein.

218. Poewe W. 2008. Non-motor symptoms in Parkinson's disease. Eur J Neurol 15 Suppl 1:14-20.

219. Hoehn MM, Yahr MD. 1967. Parkinsonism: onset, progression and mortality. Neurology 17(5):427-442.

220. ANHANG Literaturverzeichnis XXI Richard IH, Papka M, Rubio A, Kurlan R. 2002. Parkinson's disease and dementia with Lewy bodies: one disease or two? Mov Disord 17(6):1161-1165.

221. Granieri E, Carreras M, Casetta I, Govoni V, Tola MR, Paolino E, Monetti VC, De Bastiani P. 1991. Parkinson's disease in Ferrara, Italy, 1967 through 1987. Arch Neurol 48(8):854-857.

222. Chaudhuri KR, Odin P, Antonini A, Martinez-Martin P. 2011. Parkinson's disease: The non-motor issues. Parkinsonism Relat Disord.

223. Fingerklopfen (Patient berührt in rascher Reihenfolge und bei größtmöglicher Amplitude und mit jeder Hand gesondert den Daumen mit dem Zeigefinger) – je rechts und links. 0. Normal.

224. Handbewegungen (Patient öffnet und schließt die Hände in rascher Reihenfolge bei größtmöglicher Amplitude und mit jeder Hand gesondert) – je rechts und links. 0. Normal.

225. Weksler ME, Relkin N, Turkenich R, LaRusse S, Zhou L, Szabo P. 2002. Patients with Alzheimer disease have lower levels of serum anti-amyloid peptide antibodies than healthy elderly individuals. Exp Gerontol 37(7):943-948.

226. Bard F, Cannon C, Barbour R, Burke RL, Games D, Grajeda H, Guido T, Hu K, Huang J, Johnson-Wood K, Khan K, Kholodenko D, Lee M, Lieberburg I, Motter R, Nguyen M, Soriano F, Vasquez N, Weiss K, Welch B, Seubert P, Schenk D, Yednock T. 2000. Peripherally administered antibodies against amyloid beta- peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat Med 6(8):916-919.

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228. Duran R, Barrero FJ, Morales B, Luna JD, Ramirez M, Vives F. 2010. Plasma alpha- synuclein in patients with Parkinson's disease with and without treatment. Mov Disord 25(4):489-493.

229. Li QX, Mok SS, Laughton KM, McLean CA, Cappai R, Masters CL, Culvenor JG, Horne MK. 2007b. Plasma alpha-synuclein is decreased in subjects with Parkinson's disease. Exp Neurol 204(2):583-588.

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233. Quantitative assay of immunoglobulin G. Immunochemistry 8(9):871-874.

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235. Porat YB, Zan-Bar I, Ravid A. 1995. Quantitative dot-blot assay for low titer anti- lipopolysaccharide antibodies in human plasma. J Immunol Methods 180(2):213-218.

236. Haltungsstabilität (Reaktion auf plötzliches Verlagern nach hinten durch Ziehen an den Schultern des Patienten; der mit geöffneten Augen und leicht auseinander stehenden Füßen geradesteht. Der Patient ist darauf vorbereitet). 0. Normal.

237. Mire-Sluis AR, Barrett YC, Devanarayan V, Koren E, Liu H, Maia M, Parish T, Scott G, Shankar G, Shores E, Swanson SJ, Taniguchi G, Wierda D, Zuckerman LA. 2004. Recommendations for the design and optimization of immunoassays used in the detection of host antibodies against biotechnology products. J Immunol Methods 289(1-2):1-16.

238. Literaturverzeichnis VI Barbour R, Kling K, Anderson JP, Banducci K, Cole T, Diep L, Fox M, Goldstein JM, Soriano F, Seubert P, Chilcote TJ. 2008. Red blood cells are the major source of alpha-synuclein in blood. Neurodegener Dis 5(2):55-59.

239. Du Y, Dodel R, Hampel H, Buerger K, Lin S, Eastwood B, Bales K, Gao F, Moeller HJ, Oertel W, Farlow M, Paul S. 2001. Reduced levels of amyloid beta-peptide antibody in Alzheimer disease. Neurology 57(5):801-805.

240. Murray IV, Giasson BI, Quinn SM, Koppaka V, Axelsen PH, Ischiropoulos H, Trojanowski JQ, Lee VM. 2003. Role of alpha-synuclein carboxy-terminus on fibril formation in vitro. Biochemistry 42(28):8530-8540.

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242. Mein besonderer Dank gilt Frau Dr. sc. hum. Daniela Besong-Agbo, die diese Arbeit mit ihrem unermüdlichen Engagement und ihrer konstruktiven wissenschaftlichen Betreuung überhaupt erst möglich gemacht hat. Zu dem sind Frau Christine Forbach und Herr Andreas Kautz zu nennen, auf deren hilfreiche Unterstützung ich mich bei der praktischen Laborarbeit immer verlassen konnte.

243. Sehr instabil; neigt dazu, spontan das Gleichgewicht zu verlieren.

244. Lacroix-Desmazes S, Kaveri SV, Mouthon L, Ayouba A, Malanchere E, Coutinho A, Kazatchkine MD. 1998. Self-reactive antibodies (natural autoantibodies) in healthy individuals. J Immunol Methods 216(1-2):117-137.

245. Kostka M, Hogen T, Danzer KM, Levin J, Habeck M, Wirth A, Wagner R, Glabe CG, Finger S, Heinzelmann U, Garidel P, Duan W, Ross CA, Kretzschmar H, Giese A. 2008. Single particle characterization of iron-induced pore-forming alpha- synuclein oligomers. J Biol Chem 283(16):10992-11003.

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249. Mandelkow E, von Bergen M, Biernat J, Mandelkow EM. 2007. Structural principles of tau and the paired helical filaments of Alzheimer's disease. Brain Pathol 17(1):83-90.

250. Stößt sich an den Armlehnen hoch.

251. Studie bereit erklärt haben. Ohne sie wäre diese Arbeit nicht möglich gewesen.

252. Weiß C. 2010. Studien zu Diagnostik und Prävention. In: Weiß C, editor. Basiswissen Medizinische Statistik. Heidelberg: Springer Medizin Verlag. p 287-302.

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254. ANHANG Literaturverzeichnis XVII Maroteaux L, Campanelli JT, Scheller RH. 1988. Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J Neurosci 8(8):2804- 2815.

255. Murphy DD, Rueter SM, Trojanowski JQ, Lee VM. 2000. Synucleins are developmentally expressed, and alpha-synuclein regulates the size of the presynaptic vesicular pool in primary hippocampal neurons. J Neurosci 20(9):3214-3220.

256. Hughes AJ, Daniel SE, Ben-Shlomo Y, Lees AJ. 2002. The accuracy of diagnosis of parkinsonian syndromes in a specialist movement disorder service. Brain 125(Pt 4):861-870.

257. Mannisto T, Surcel HM, Bloigu A, Ruokonen A, Hartikainen AL, Jarvelin MR, Pouta A, Vaarasmaki M, Suvanto-Luukkonen E. 2007. The effect of freezing, thawing, and short-and long-term storage on serum thyrotropin, thyroid hormones, and thyroid autoantibodies: implications for analyzing samples stored in serum banks. Clin Chem 53(11):1986-1987.

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259. Manning-Bog AB, McCormack AL, Li J, Uversky VN, Fink AL, Di Monte DA. 2002. The herbicide paraquat causes up-regulation and aggregation of alpha-synuclein in mice: paraquat and alpha-synuclein. J Biol Chem 277(3):1641-1644.

260. Hanley JA, McNeil BJ. 1982. The meaning and use of the area under a receiver operating characteristic (ROC) curve. Radiology 143(1):29-36.

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263. Greffard S, Verny M, Bonnet A, Seilhean D, Hauw J, Duyckaerts C. 2008. The proportion of neurons containing Lewy bodies remains stable with time in the substantia nigra. A proposed model of neuronal death in relation to Lewy bodies. Clin Neuropathol 27:179.

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